Color-Coded Polymeric Particles of Predetermined Size for Therapeutic and/or Diagnostic Applications and Related Methods

ABSTRACT

Various embodiments are directed to color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures. In various embodiments, the color-coded and size-calibrated polymeric particles can be employed in any particle-mediated procedure, including as embolic agents, dermal fillers, and various implantable devices for a broad range of clinical and cosmetic applications. The incorporation of a particular chromophore formulation that correlates with a pre-determined size specificity for implantable and loadable polymeric particles (“color-coded and size-calibrated”) enables the visual detection and identification of particles exhibiting a particular size of interest, and minimizes the probability of user-introduced or procedural errors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent application Ser. No. 11/924,674, filed on Oct. 26, 2007, currently pending, which:

is a continuation-in-part of U.S. patent application Ser. No. 11/257,535, filed Oct. 25, 2005, currently pending, which claims the benefit of U.S. Provisional Patent Applications: No. 60/621,729, filed Oct. 25, 2004; and the No. 60/684,307, filed May 24, 2005; and

also which claims the benefit of U.S. Provisional Patent Application No. 60/962,015, filed Jul. 25, 2007;

the entire disclosures of which are incorporated herein by reference.

TECHNICAL FIELD

This disclosure relates to various polymeric particles incorporating chromophores and other agents of interest that can be employed as implantable devices in animal subjects, for various diagnostic and therapeutic applications.

BACKGROUND

Various cosmetic, clinical, and interventional procedures involve in vivo administration of synthetic particles, manufactured in various sizes and compositions. For example, various blends of polymeric embolic particles can be introduced into the lumen of blood vessels to intentionally impede blood flow through various tissues/organs affected with physical trauma, tumor, or any condition in which blood-flow intervention can provide an effective and noninvasive form of temporary or permanent mode of therapy (“embolization”).

In general, the manufactured products containing such synthetic particles require further manipulation by the practitioner prior to in vivo administration. The particle-based products provided by a manufacturer need to be combined with other reagents in order to make a final sample preparation suitable for in vivo administration. Substantial human errors can be inadvertently introduced during the preparatory procedures that may increase the overall risk associated with performing a given treatment. Practitioners need particles formulated to minimize various types of risks introduced during sample preparations for various particle-mediated diagnostic and/or therapeutic applications.

SUMMARY OF THE INVENTION

Various embodiments are directed to color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures. In various embodiments, the color-coded and size-calibrated polymeric particles can be employed in any particle-mediated procedure, including as embolic agents, dermal fillers, and various implantable devices for a broad range of clinical and cosmetic applications. The incorporation of a particular chromophore formulation that correlates with a pre-determined size specificity for implantable and loadable polymeric particles (“color-coded and size-calibrated”) enables the visual detection and identification of particles exhibiting a particular size of interest, and minimizes the probability of user-introduced or procedural errors.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of an exemplary color-coded and size-calibrated polymeric particle comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising a polyphosphazene coating of formula I.

FIG. 2 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within reactive dye molecules before reacting with acrylate-based hydrogels in the presence of a coupling agent.

FIG. 3 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within acrylate-based hydrogels before reacting with reactive dye molecules.

FIG. 4 is a schematic of an interventional occlusion of a hypothetical blood vessel employing particles of at least three different diameter sizes, each set of particles labeled according to a different color scheme.

DETAILED DESCRIPTION A. Definitions

In addition to the definition of terms provided below, the terms “a” or “an” can mean one or more of the referenced subject matter.

The term “particle-mediated procedure” refers to any procedure that involves the utilization of disclosed particles in order to facilitate a diagnostic purpose and/or a therapeutic purpose. Exemplary particle-mediated procedures include various intravascular interventional procedures (“embolization”) involving in vivo administration of synthetically made particles of various compositions for reducing or stopping blood flow into the affected tissue/organ, including: for controlling gastrointestinal bleeding of any cause, for controlling bleeding into the abdomen or pelvis from any physical trauma injuries, for controlling bleeding resulting from long menstrual periods or heavy menstrual bleeding caused by uterine fibroid tumors, for occluding vessels that are supplying blood to tumors, for eliminating arteriovenous malformation (AVM) or arteriovenous fistula (AVF) caused by abnormal connection or connections between arteries and veins, for treating various types of aneurysms, and various other conditions and diseases suitable for such particle-mediated interventional procedures. The contemplated “particle-mediated procedures” include any procedure in which a benefit can be conferred by the targeted delivery of particles of interest for any form of therapy, including various diagnostic, therapeutic, and cosmetic applications. The particles can be delivered to any tissue or organ of a recipient. The type of optimal particles (size range, color, composition) suitable for a given condition under contemplation would need to be determined by the practitioner.

The terms “particle(s),” “color-coded particles,” and “color-coded and size-calibrated particles” can be used interchangeably to refer to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 10 μm to approximately 1500 μm, that can be employed for any particle-based procedure, and includes various embolic particles and dermal-filler particles. In various embodiments, the particles refer to substantially polymeric bodies shaped or formed as substantially spherical or ellipsoid articles manufactured to a particular size or diameter of interest and incorporating one or more chromophores of interest in order to produce a set of particles characterized by a particular predetermined size and color.

The term “embolic particles” refers to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 10 μm to approximately 1500 μm, suitable for any embolization procedure, and exemplifies “color-coded and size-calibrated particles.” In producing embolic particles of a broad size range, each set of particles calibrated for a particular size/dimension can be manufactured to incorporate a particular color desired to match the size-calibrated particles so that each set of such particles can be visually identified by the particular color exhibited (“color-coded”). Suitable embolic particles can be composed of any material amendable to controlled manufacturing and production specifications according to shaping and sizing requirements. Embolic particles are typically suspended in a transport medium containing various components that stabilize the particles during storage and shipment by manufacturers. In particular, the color-coded and size-calibrated particles can be employed as embolic agents for treating hypertrophic obstructive cardiomyopathy (HCM), having an average diameter size ranging from approximately 50 μm to approximately 90 μm, preferably from approximately 60 μm to approximately 80 μm, and most preferably from approximately 70 μm to approximately 75 μm.

The term “dermal-filler particles” refers to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 50 μm to approximately 500 μm, from approximately 50 μm to approximately 400 μm, from approximately 50 μm to approximately 300 μm, from approximately 50 μm to approximately 200 μm, suitable for any cosmetic application procedure, and exemplifies “color-coded and size-calibrated particles.” Suitable dermal-filler particles can be composed of any material amendable to controlled manufacturing and production specifications according to shaping and sizing requirements. Dermal-filler particles can be administered to a recipient in need of cosmetic and/or therapeutic enhancement in appearance, including the removal of wrinkles, dermal texture imperfections, dermal blot clots, dermal age-related disease or damage, and other equivalent conditions known by persons skilled in the art of dermal cosmetic enhancement and dermal diagnostic/clinical/therapeutic applications. Mixtures of chromophores formulated to resemble various skin tones can be incorporated into the acrylate-based hydrogel cores of color-coded and size-calibrated particles manufactured for use as dermal fillers.

The term “acrylate-based hydrogel” refers to any polymer chain, formed in part or entirely, through the polymerization of an acrylate based monomer and (optionally) through subsequent and/or parallel reactions, can be three-dimensionally crosslinked, and having pendant side groups to confer the resulting cross-linked polymeric network with a substantial affinity for particular solvents, such as water, and to enable swelling.

The term “gel” refers to an elastic colloid or polymeric network capable of expanding throughout the volume by the absorption of fluid. The polymer network can be a network formed by covalent bonds or by physical aggregation with region of local order acting as network junctions. Both by weight and volume, gels can be mostly liquid in composition and thus exhibit densities similar to that of liquids, however, gels have the structural coherence of a solid. The term “hydrogel” refers to a polymeric network capable of absorbing water.

The term “crosslink” refers to a small region in a macromolecule from which at least three chains emanate, and formed by reactions involving sites or groups on existing macromolecules or by interactions between existing macromolecules. The small region may be an atom, a group of atoms, or a number of branch points connected by bonds, groups of atoms, or oligomeric chains. In general, a crosslink is a covalent structure but the term can describe sites of weaker chemical interactions, portions of crystallites, and even physical entanglements.

The term “chromophores” refers to any molecule that can absorb certain wavelengths of visible light, and can transmit or reflect other wavelengths as understood by persons skilled in the art, and includes various nontoxic pigments and dyes of medical grade that can be incorporated into food and/or medical devices for implantation into human and/or animal subjects without imposing the risk of substantial harm The chromophores suitable for incorporation into particles of interest include dyes that have been approved or have been exempt from certification by the FDA, which are listed under TITLE 21—FOOD AND DRUGS, CHAPTER I—FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES, SUBCHAPTER A, GENERAL, PART 73 LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION, Subpart D—Medical Devices, the disclosure of which is incorporated herein by reference.

The term “incorporate” refers to any process involving the physical or chemical affixation of one or more species, including atoms, molecular entities, agents such as dyes, oligo- and polymeric species together. For example, the term refers to processes involving impregnation, precipitation, covalent binding, grafting in- or onto, fixing in- or onto, diffusion, permeation, temporary or permanent, partial or complete localization within, around, throughout a given article.

B. Manufacturing Implantable and Loadable Polymeric Particles of Various Sizes Labeled with Chromophores to Facilitate Visual Identification

In various embodiments, the color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures are provided.

In various embodiments, the color-coded and size-calibrated polymeric particles, comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as embolic particles for mediating various interventional procedures.

In various embodiments, the color-coded and size-calibrated polymeric particles, comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as embolic agents for treating hypertrophic obstructive cardiomyopathy (HCM).

In various embodiments, the color-coded and size-calibrated polymeric particles, comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as dermal fillers.

In various embodiments, the biocompatible and loadable polymeric particles comprises an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising poly[bis(trifluoroethoxy) phosphazene] and/or a derivative thereof. The incorporation of a particular chromophore formulation that correlates with a predetermined size range of implantable and loadable polymeric particles of interest (“color-coded” particles) permit a convenient and accurate visual identification of particles of interest and minimizes user-introduced errors.

C. Manufacturing a Hydrogel Core

1. Acrylate-Based Hydrogels

FIG. 1 is a schematic of an exemplary color-coded and size-calibrated polymeric particle comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising a polyphosphazene coating of formula I. In FIG. 1, a hypothetical particle 100 comprising an acrylate-based hydrogel core 110 and an outer shell 120 is shown. The acrylate-based hydrogel core 110 can be manufactured to incorporate various chromophores present in a sufficient amount to permit the detection of a “color” by a human eye or by an instrument. The total amount of chromophores sufficient to be visually detected can vary depending on particular chromophores selected. The total amount of chromophores that can be incorporated into the color-coded and size-calibrated particles can range up to about 20%, about 15%, about 10%, about 8%, about 6%, about 5%, or about 2.5% of the total dry weight of the hydrogel. An outer shell 120 comprising at least one polyphosphazene of formula I, can be formed on the surface of the acrylate-based hydrogel core 110 to provide a biocompatible coating layer.

In various embodiments, the color-coded and size-calibrated polymeric particles can be manufactured to be substantially uniform in size. For example, the smallest average diameter of a set of particles for a first product line can be about 10 μm, and the largest average diameter of a set of particles for a second product line can be about 1500 μm. The average diameter size range of particles of interest can be selected from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm. Suitable range in average diameter size of a particle of interest include: from about 20 μm to about 1500 μm; from about 20 μm to about 1200 μm; from about 20 μm to about 1000 μm; from about 20 μm to about 900 μm; from about 20 μm to about 800 μm; from about 20 μm to about 700 μm; from about 20 μm to about 600 μm; from about 20 μm to about 500 μm; from about 20 μm to about 400 μm; from about 20 μm to about 300 μm; from about 20 μm to about 200 μm; from about 20 μm to about 175 μm; from about 20 μm to about 150 μm; from about 20 μm to about 120 μm; from about 20 μm to about 80 μm; and from about 20 μm to about 40 μm. Suitable range in average diameter size of a particle of interest include: from about 30 μm to about 1500 μm; from about 30 μm to about 1300 μm; from about 30 μm to about 3000 μm; from about 30 μm to about 900 μm; from about 30 μm to about 800 μm; from about 30 μm to about 700 μm; from about 30 μm to about 600 μm; from about 30 μm to about 500 μm; from about 30 μm to about 400 μm; from about 30 μm to about 300 μm; from about 30 μm to about 300 μm; from about 30 μm to about 175 μm; from about 30 μm to about 150 μm; from about 30 μm to about 130 μm; from about 30 μm to about 80 μm; and from about 30 μm to about 40 μm. The color-coded and size-calibrated polymeric particles can be calibrated to a predetermined deviation tolerance of less than or equal to about ±5%, less than or equal to about ±10%, less than or equal to about ±15%, less than or equal to about ±20%, less than or equal to about ±25%, less than or equal to about ±30%, or less than or equal to about ±35% from the design specification. In a preferred embodiment, the color-coded and size-calibrated polymeric particles can be manufactured to exhibit a narrow size distribution proportional to the average size of the particles. For example, the particles within the range from about 700 μm to about 1000 μm can vary less than or equal to only about ±3-5% from the design specification, whereas particles within the size range from about 40 μm to about 100 μm can vary less than or equal to about ±20-25% from the design specification.

In another embodiment, the color-coded and size-calibrated polymeric particles can be manufactured to exhibit uniformity in shape, and preferably, the particles can be manufactured to be substantially spherical in shape.

Various methods for manufacturing acrylate-based hydrogel cores have been previously described by the present Applicants in U.S. Patent Publication Nos. 2006/0088476 and 2008/0113029, the entire disclosures of which are incorporated herein by reference.

2. Acrylate-Based Hydrogels as the Core Component of Color-Coded and Size-Calibrated Particles

The color-coded and size-calibrated polymeric particles comprise an acrylate-based hydrogel, as a core component, that can be manufactured utilizing various polymers known to persons skilled in the art, including polymers selected from poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate) (PMMA), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), or an equivalent known by persons skilled in the art, a copolymer thereof, and/or a combination thereof.

3. Exemplary Chromophores and Methods for Incorporating into Acrylate-Based Hydrogels

FIG. 2 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within reactive dye molecules before reacting with acrylate-based hydrogels in the presence of a coupling agent. In FIG. 2, a suitable reactive dye 200 can be amino-activated with an aliphatic diamine (ethylene diamine) 210 to form an aliphatic amino group within the reactive dye 220, which can be reacted with a hypothetical acrylate-based hydrogel 230 in the presence of a coupling promoter agent 240, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to produce color-coded and size-calibrated particles 250 incorporated with reactive dye molecules by a stable covalent linkage.

Table of Exemplary Reactive Dyes:

Table of Exemplary Reactive Dyes: Monochlorotriazines R¹ = chromophore R² = 2^(nd) chromophore or any other

Mono- fluorochlorotriazines R = chromophore

Dichlorotriazines R = chromophore

Dichloroquinoxaline R¹ = chromophore or any other R² = chromophore or any other R³ = chromophore or any other R⁴ = chromophore or any other

Trichloropyrimidine R = chromophore

Vinyl sulfone R = chromophore

Vinyl amide R¹ = chromophore or any other R² = chromophore or any other R³ = chromophore or any other R⁴ = chromophore or any other

Exemplary reactive dyes used in production (FDA exempt from certification): Reactive Red 11 (dichlorotriazine), Reactive Yellow 86 (dichlorotriazine), Reactive Blue 4 (dichlorotriazine), Reactive Black 5 (vinyl sulfone), Reactive Red 180 (vinyl sulfone), Reactive Yellow 15 (vinyl sulfone), Reactive Blue 19 (vinyl sulfone), Reactive Blue 21 (vinyl sulfone), Reactive Blue 163 (vinyl sulfone), Reactive Orange 78 (vinyl sulfone), and others known to persons skilled in the art.

Exemplary spacer molecules to link the reactive dye to the polymer in the hydrogel include any di-functional, tri-functional, or multi-functional species, the functional species comprising a nucleophilic group, including H₂N—(CH₂)_(n)—NH₂ (n≥2) [in production n=2 (ethylene diamine)], [H—₂N—(CH₂)_(n)]₃—CH (n≥1), [H₂N—(CH₂)_(n)]₄—C (n≥1). These examples can be accordingly reformulated by replacing the nucleophilic group H₂N— with —OH, —SH or any other arbitrary nucleophilic group.

An exemplary formula for an amino activator spacer molecule is provided by: H₂N—CH₂—R—CH₂—NH₂, wherein the R is an alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene; includes carrying organic and heteroorganic side groups (such as hydroxyl, silyl, thiol, sulfonyl, sulfoxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate).

FIG. 3 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within acrylate-based hydrogels before reacting with reactive dye molecules. In the first reaction of FIG. 3, the carboxylic acid groups of the PMAA 300, as an hypothetical acrylate-based hydrogel, can be amino-activated by reacting with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) 310 in the presence of an aliphatic diamine (ethylene diamine) 320. In the second reaction of FIG. 3, the resulting free amino group within the activated acrylate-based hydrogel 330 can react with the reactive dyes 340 to produce the color-coded and size-calibrated particles 350 incorporated with reactive dye molecules by a stable covalent linkage.

Alternatively, active anchor groups can be created within the PMAA core of color-coded and size-calibrated particles during the polymerization process of PMMA. For example, co-polymerization of MMA in the presence of a small amount (about 1-10%) of amino (—NH₂) or hydroxyl (—OH) groups (or protected forms of both) containing unsaturated species can generate active anchor groups so that reactive dyes can be directly bound to the hydrogel core without prior activation without requiring ethylene diamine via EDC to activate the hydrogel core or amino activation of dye molecules. Exemplary co-polymers include unsaturated alcohols, unsaturated amines, and unsaturated thiols.

The generalized formula for unsaturated alcohols is R⁵O—R¹—CR²═CR³R⁴

wherein R¹ is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);

wherein R², R³ and/or R⁴ enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and

wherein R⁵ includes hydrogen or any protecting group.

Exemplary unsaturated alcohols include vinyl alcohol (H₂C═CH—OH) or derivatives [H₂C═CH—(CH₂)_(n)—OH] (n≥1) [n=1: allyl alcohol].

The generalized formula for unsaturated amine is: R⁵HN—R¹—CR²═CR³R⁴

wherein R¹ is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);

wherein R², R³ and/or R⁴ enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and

wherein R⁵ includes hydrogen or any protecting group.

Exemplary unsaturated amines include vinyl amine (H₂C═CH—NH₂) or derivatives [H₂C═CH—(CH₂)_(n)—NH₂] (n≥1).

The generalized formula for unsaturated thiols is R⁵S—R¹—CR²═CR³R⁴

wherein R¹ is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);

wherein R², R³ and/or R⁴ enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and

wherein R⁵ includes hydrogen or any protecting group.

Exemplary unsaturated amines include vinyl mercaptane (H₂C═CH—SH) or derivatives [H₂C═CH—(CH₂)_(n)—SH] (n≥1) [n=1: allyl mercaptane].

4. Exemplary Agents of Interest

In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate any compound/agent of interest suitable for various therapeutic and/or diagnostic applications.

In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate any bioactive and pharmaceutical agents, such as peptides, proteins, hormones, carbohydrates, polysaccharides, nucleic acids, lipids, vitamins, steroids, organic or inorganic drugs, and/or equivalents, and combinations thereof.

In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate various fluorescent dyes, radiopaque reagents, and/or equivalents to permit contemporaneous monitoring, and combinations thereof.

In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate magnetic, diamagnetic, paramagnetic, ferromagnetic and/or antiferromagnetic elements to impart certain magnetic properties.

In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate various excipients, such as dextranes, other sugars, polyethylene glycol, glucose, and various salts. The term “contrast agent” refers to various compounds, suspended in contrast medium/media, that enables radiopaque visibility by highlighting specific tissue/organ of interest during various diagnostic medical imaging examinations and/or treatment procedures that require simultaneous monitoring, by various means including: x-ray exams, computed tomography scans, and magnetic resonance imaging. Exemplary contrast agents include iobitridol, iodixanol, iomeprol, iopamidol, iopentol, iopromide, ioversol, and other iodine-formulated compositions, which have iodine concentrations between about 240 mg/ml to about 400 mg/ml, or more. In general, as the average size of particles increases, a larger volume of contrast medium may be required to sufficiently saturate the particles with an iodine threshold level necessary to provide adequate radiopaque visibility when monitoring particle transport following in vivo administration.

In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate barium sulfate, which can be utilized for increasing the density of the particle, so that the particle can be properly suspended within a dense medium, such as a contrast agent-containing solution, for modulating or enhancing the added chromophore by creating varying degrees of translucency, contributing to the intensity of the color perceived, for changing the elastic and mechanic properties of a particle as an inelastic component, and/or for increasing the radiopaqueness of a particle, without the use of separate contrast agent, capable of acting as a contrast agent in itself.

D. High Molecular Weight Polyphosphazenes of Formula I as an Outer Shell for Color-Coded and Size-Calibrated Polymeric Particles

The definition for high molecular weight polyphosphazenes of formula I and methods for coating acrylate-based hydrogel cores have been previously described by the present Applicants in U.S. Patent Publication Nos. 2006/0088476 and 2008/0113029, the entire disclosures of which are incorporated herein by reference.

Various embodiments are directed to color-coded and size-calibrated particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes having the general formula (I):

-   -   in which the n value is an integer from 2 to ∞;     -   R¹ to R⁶ are independently selected from the group consisting         of:     -   a substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy,         silyl, silyloxy, alkylsulfonyl, alkyl amino, dialkyl amino,         ureido, carboxylic acid ester, alkylmonoamidine,         alkylbisamidine, alkoxymonoamidine, alkoxybisamidine; and an         amino;     -   a heterocyclic alkyl group with at least one nitrogen,         phosphorus, oxygen, sulfur, or selenium as a heteroatom;     -   a heteroaryl group with at least one nitrogen, phosphorus,         oxygen, sulfur, or selenium as the heteroatom;     -   a nucleotide or a nucleotide residue;     -   a biomacromolecule; and     -   a pyrimidine or a purine base.

Suitable substituents for R¹ to R⁶ can be independently selected from the group consisting of: halide substituents, such as fluorine, chlorine bromine, or iodine; pseudohalide substituents, such as cyano (—CN), isocyano (—NC), thiocyano (—SCN), isothiocyano (—NCS), cyanato (—OCN), isocyanato (—NCO), or azido (—N₃) groups; substituents such as nitro- (—NO₂) or nitrito (—NO) groups; partially substituted alkyl groups, such as haloalkyl; heteroaryl such as imidazoyl, oxazolyl, thiazolyl, or pyrazolyl derivatives; and purine and pyrimidine bases such as guanidines, amidines or other ureido derivatives of the base structure.

As used herein, alkyl (R), alkoxy (—OR), alkylsulfonyl (—SO2R), alkyl amino (—NHR), dialkyl amino (—NR₂), carboxylic acid ester (-(alkadiyl)C(O)OR or -alkadiyl)OC(O)R)), ureido (—NHC(O)NH₂, —NRC(O)NH₂, —NHC(O)NHR, —NRC(O)NHR, —NHC(O)NR₂, —NRC(O)NR₂, and their alkadiyl-linked analogs), alkylmonoamidine (including —N═C(NR₂)R, —(alkadiyl)N═C(NR₂)R, —C(NR₂)═NR, and -(alkadiyl)C(NR₂)═NR), alkylbisamidine (including —N═C(NR₂)₂, -(alkadiyl)N═C(NR₂)₂, —NRC(NR₂)═NR, and -(alkadiyl)NRC(NR₂)═NR), alkoxymonoamidine (—O(alkadiyl)N═C(NR₂)R, —OC(NR₂)═NR, and —O(alkadiyl)C(NR₂)═NR)), and alkoxybisamidine (—O(alkadiyl)N═C(NR₂)₂. —O(alkadiyl)NRC(NR₂)—NR, and —O(alkadiyl)NRC(NR₂)═NR) moieties are defined by the corresponding formula shown, in which R can be selected independently from a linear, branched, and/or cyclic (“cycloalkyl”) hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyl moieties, having from 1 to about 20 (for example, from 1 to about 12, or 1 to about 6) carbon atoms.

The inclusion of alkenyl and alkynyl moieties provides, among other things, the capability to cross-link the polyphosphazene moieties to any extent desired. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have linear, branched and/or cyclic portions (e.g. 1-ethyl-4-methyl-cyclohexyl).

According to this definition and usage (supra), specific examples of R (alkyl) groups include unsubstituted alkyl, substituted alkyl such as halo-substituted alkyl (haloalkyl), unsubstituted alkenyl, substituted alkenyl such as halo-substituted alkenyl, and unsubstituted alkynyl, and substituted alkynyl such as halo-substituted alkynyl.

Furthermore, these examples of R (alkyl) provide that the alkoxy (OR) substituents can be unsubstituted alkoxy (“alkyloxy”), substituted alkoxy such as halo-substituted alkoxy (haloalkoxy), unsubstituted alkenyloxy, substituted alkenyloxy such as halo-substituted alkenyloxy, unsubstituted alkynyloxy, and substituted alkynyloxy such as halo-substituted alkynyloxy. In this aspect, vinyloxy and allyloxy can be useful.

A silyl group is a —SiR₃ group and a silyloxy group is an —OSiR₃ group, where each R moiety is selected independently from the R groups defined supra. That is, R in each occurrence is selected independently from a linear, branched, and/or cyclic (“cycloalkyl”) hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyl moieties, having from 1 to about 20 (for example, from 1 to about 12, or 1 to about 6) carbon atoms.

Unless otherwise specified, any R group can be unsubstituted or substituted independently with at least one substituent selected from a halogen (fluorine, chlorine, bromine, or iodine), an alkyl, an alkylsulfonyl, an amino, an alkylamino, a dialkylamino, an amidino (—N═C(NH₂)₂), an alkoxide, or an aryloxide, any of which can have up to about 6 carbon atoms, if applicable. Thus, the term substituted “alkyl” and moieties which encompass substituted alkyl, such as “alkoxy,” include haloalkyl and haloalkoxy, respectively, including any fluorine-, chlorine-, bromine-, and iodine-substituted alkyl and alkoxy. Thus, terms haloalkyl and haloalkoxy refers to alkyl and alkoxy groups substituted with one or more halogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof.

Unless otherwise indicated, the term “aryl” means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms, which may be a single ring moiety, or may contain multiple rings bound or fused together. Examples of aryl moieties include, but are not limited to, phenyl, anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, 1,2,3,4-tetrahydro-naphthalene, tolyl, and the like, any of which having up to about 20 carbon atoms. An aryloxy group refers to an —O(aryl) moiety.

The terms haloaryl and haloaryloxy refer to aryl and aryloxy groups, respectively, substituted with one or more halogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof.

A heterocyclic alkyl group with at least one nitrogen as a heteroatom refers to a non-aromatic heterocycle and includes a cycloalkyl or a cycloalkenyl moiety in which one or more of the atoms in the ring structure is nitrogen rather than carbon, and which may be monocyclic or multicyclic, and may include exo-carbonyl moieties and the like. Examples of heterocyclic alkyl group with nitrogen as a heteroatom include, but are not limited to, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyrimidinyl, morpholinyl, aziridinyl, imidazolidinyl, 1-pyrroline, 2-pyrroline, or 3-pyrroline, pyrrolidinonyl, piperazinonyl, hydantoinyl, piperidin-2-one, pyrrolidin-2-one, azetidin-2-one, and the like. Thus, these groups include heterocyclic exocyclic ketones as well.

A heteroaryl group with at least one nitrogen as the heteroatom refers to an aryl moiety in which one or more of the atoms in the ring structure is nitrogen rather than carbon, and which may be monocyclic or multicyclic. Examples of heterocyclic alkyl group with nitrogen as a heteroatom include, but are not limited to, acridinyl, benzimidazolyl, quinazolinyl, benzoquinazolinyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxazolyl or oxadiazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, triazinyl, and the like. In this aspect, this disclosure includes or encompasses chemical moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecules, and biomacromolecules. For example, this disclosure encompasses a number of pharmaceutical agents available with the tetrazole group (for example, losartan, candesartan, irbesartan, and other Angiotensin receptor antagonists); the triazole group (for example, fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, posaconazole, and other antifungal agents); diazoles (for example, fungicides such as Miconazole, Ketoconazole, Clotrimazole, Econazole, Bifonazole, Butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, and the like); and imidazoles (histidine, histamine, and the like). Thus in one aspect, some of the R¹ to R⁶ moieties in the formula I can encompass chemical moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecules, and biomacromolecules.

A heterocyclic alkyl group with at least one phosphorus, oxygen, sulfur, or selenium as a heteroatom refers to a non-aromatic heterocycle and includes a cycloalkyl or a cycloalkenyl moiety in which one or more of the atoms in the ring structure is phosphorus, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or multicyclic, and may include exo-carbonyl moieties and the like. Similarly, a heteroaryl group with at least one phosphorus, oxygen, sulfur, or selenium as the heteroatom refers to an aryl moiety in which one or more of the atoms in the ring structure is phosphorus, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or multicyclic. Examples of heterocyclic alkyl groups or heteroaryls with phosphorus, oxygen, sulfur, or selenium as a heteroatom include, but are not limited to, substituted or unsubstituted ethylene oxide (epoxides, oxiranes), oxirene, oxetane, tetrahydrofuran (oxolane), dihydrofuran, furan, pyran, tetrahydropyran, dioxane, dioxin, thiirane (episulfides), thietane, tetrahydrothiophene (thiolane) dihydrothiophene, thiophene, thiane, thiine (thiapyrane), oxazine, thiazine, dithiane, dithietane, and the like. Thus, these groups include all isomers, including regioisomers of the recited compounds. For example, these groups include 1,2- and 1,3-oxazoles, thiazoles, selenazoles, phosphazoles, and the like, which include different heteroatoms from the group 15 or group 16 elements.

Additionally, if desired, polymers other than the poly[bis(trifluoroethoxy) phosphazene] and/or its derivative may be included and/or combined with in the particle. Examples of polymers may include poly(lactic acid), poly(lactic-co-glycolic acid), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyorthoesters, polyacetals, polycyanoacrylates, and polyurethanes. Other polymers include polyacrylates, ethylene-vinyl acetate co-polymers, acyl substituted cellulose acetates and derivatives thereof, degradable or non-degradable polyurethanes, polystyrenes, polyvinylchloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonated polyolefins, and polyethylene oxide. Examples of polyacrylates include, but are not limited to, acrylic acid, butyl acrylate, ethylhexyl acrylate, methyl acrylate, ethyl acrylate, acrylonitrile, methyl methacrylate, TMPTA (trimethylolpropane triacrylate), and the like. One may incorporate the selected compounds by any means known in the art, including diffusing, inserting or entrapping the additional compounds in the matrix of an already formed particle or by adding the additional compound to a polymer melt or to a polymer solvent in the preparation of the particle such as described herein.

The particle may be coated with an additional polymer layer or layers, including polymers such as those mentioned hereinabove. Further, PTFEP or derivatives thereof, may be used to form such a coating on a particle formed of other suitable polymers or copolymers known or to be developed in the art. Preferably, when coating a particle such as a microparticle, PTFEP is applied as a coating on a microparticle(s) formed of an acrylic-based polymer as set forth in further detail below.

E. Various Methods for Utilizing Color-Coded and Size-Calibrated Polymeric Particles

FIG. 4 is a schematic of an interventional occlusion of a hypothetical blood vessel employing particles of at least three different diameter sizes, each set of particles labeled according to a different color scheme. In FIG. 4, a hypothetical blood vessel 400 that can transport blood from point 405 to point 410 as shown. If occlusion of blood vessel 400 at point 410, for example, is necessary for treatment, efficient occlusion can be achieved by deploying a first set A of smallest particles such as 420 and 422, followed immediately by a second set B of intermediate particles such as 430 and 432, followed immediately by a third set C of largest particles such as 440 and 442 of a given range of particles calibrated to a particular size of interest.

A method of selective embolization at a site in need of, the method comprising administering color-coded and size-calibrated particles described herein to a patient in need of.

All publications and patents mentioned in this disclosure are incorporated herein by reference in their entireties, for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the presently described methods, compositions, articles, and processes. The publications discussed throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention. Should the usage or terminology used in any reference that is incorporated by reference conflict with the usage or terminology used in this disclosure, the usage and terminology of this disclosure controls. The Abstract of the disclosure is provided to satisfy the requirements of 37 C.F.R. §1.72 and the purpose stated in 37 C.F.R. §1.72(b) “to enable the United States Patent and Trademark Office and the public generally to determine quickly from a cursory inspection the nature and gist of the technical disclosure.” The Abstract is not intended to be used to construe the scope of the appended claims or to limit the scope of the subject matter disclosed herein. Moreover, any headings are not intended to be used to construe the scope of the appended claims or to limit the scope of the subject matter disclosed herein. Any use of the past tense to describe an example otherwise indicated as constructive or prophetic is not intended to reflect that the constructive or prophetic example has actually been carried out.

Also unless indicated otherwise, when a range of any type is disclosed or claimed, for example a range of molecular weights, layer thicknesses, concentrations, temperatures, and the like, it is intended to disclose or claim individually each possible number that such a range could reasonably encompass, including any sub-ranges encompassed therein. For example, when the Applicants disclose or claim a chemical moiety having a certain number of atoms, for example carbon atoms, Applicants' intent is to disclose or claim individually every possible number that such a range could encompass, consistent with the disclosure herein. Thus, by the disclosure that an alkyl substituent or group can have from 1 to 20 carbon atoms, Applicants intent is to recite that the alkyl group have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, including any range or sub-range encompassed therein. Accordingly, Applicants reserve the right to proviso out or exclude any individual members of such a group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, if for any reason Applicants choose to claim less than the full measure of the disclosure, for example, to account for a reference that Applicants are unaware of at the time of the filing of the application.

EXAMPLES Example 1 Physical Incorporation of Indigo Dyes as Precipitates

Indigo dye can be incorporated into acrylate-based microparticles as follows. The vat can be prepared by mixing 5 g Indigo, 2.5 ml ethanol, 150 ml hot water, 6.5 ml concentrated sodium hydroxide solution and 7.5 g sodium dithionite. The mixture can be stirred for 15 minutes at 50-60° C. until the mixture converts to yellow-greenish. The concentrated solution can be given into 3 L of hot (50-60° C.) water with 3 ml of ammonia (25% solution) and additional 2 g of sodium dithionite. The amount of water can be varied from 0 to 31 to receive different color intensity. After stirring of the solution becomes yellow-greenish the particles can be added, and gently stirred for additional 15 minutes. After decanting and rinsing of the particles with water they become blue. Alternatively, Indigo red can be incorporated following the same protocol.

Example 2 Physical Incorporation of Dyes Containing Sulfonic Acid Side Groups as Precipitates

Dyes containing sulfonic acid side groups can be incorporated into acrylate-based microparticles as follows. Dyes containing sulfonic acid side groups have a high capacity in precipitating with barium ions to form a water insoluble compound. For example, 3 ml Reactive Blue 21 (20 mg/ml physiological saline) can be added to 3 ml hydrated polymethylacrylate beads (400-600 μm) in physiological saline (total volume 6 ml). The suspension can be gently shaken for 10 to 15 min to reach diffusion equilibrium. Afterwards, the aqueous phase can be removed. 5 ml 0.5 molar aqueous barium chloride can be added to the particles and shaken over 30 min at ambient temperature. The suspension was stored over night at 70° C., than extensively washed with physiological saline until the solution remained optically colorless. The solution can be substituted by 0.5 molar barium chloride and heated for 30 min to approximately 125° C. at 1.5 bar. Afterwards the particles can be extensively washed with physiological saline. Different color intensities can be prepared by varying aqueous Reactive Blue 21 concentrations from 2 to 30 mg/ml physiological saline and from 0.5 ml to 5 ml hydrated polymethylacrylate beads.

Example 3 Physical Incorporation of Dyes Containing Sulfonic Acid Side Groups as Precipitates

Dyes containing sulfonic acid side groups can be incorporated into acrylate-based microparticles as follows. Reactive Blue, Reactive Blue 4, Reactive Blue 19, Reactive Blue 163, Reactive Black 5, Reactive Yellow 86, Reactive Yellow 15, Reactive Orange 78, Reactive Red 11, Reactive Red 180, Chinolin Yellow, Allura Red AC, and any combinations thereof can be used to obtain different color shades by using mixtures of various ratios/percentage. Color intensities can be altered by varying the total dye amount (1 mg to 400 mg).

Example 4 Chemical Incorporation of Dyes to Activated Hydrogels Exhibiting Reactive Groups

A mixture of methyl methacrylate (MMA), allyl methacrylate (AMA), and the crosslinker triethyleneglycol dimethacrylate (TEGDMA) is copolymerized in presence of a radical initiator (lauroyl peroxide, LP) can be performed by suspension polymerization. For example, 200 g freshly destilled MMA, 670 mg LP, 2.875 g TEGDMA, and 10 g AMA can be mixed until a clear solution is obtained. The aqueous phase composed of 23 g polyvinylalcohol (PVA; 26/88), 5 g disodium hydrogen phosphate, and 290 mg sodium dihydrogen phosphate can be dissolved in 1000 ml deionized water. Polymerization can be performed by stirring at 130 rpm (initial 250 rpm for 5 to 10 min) at 67° C. for 1 h, than 2 h at 70° C., and finally 80° C. for 2 h. Particle sizes in the range of 50 to 1000 μm can be obtained. Hydrolysis can be performed with 5 g of the particles (taken from sieve fraction 212 to 350 μm) in 1500 ml ethylene glycol containing 75 g potassium hydroxide under reflux for 2 h. Afterwards, the particles can be washed extensively with deionized water until pH7 results. The water can be substituted by physiological saline, and osmolarity measured at 290±50 mOsmol/kg. 20 ml hydrated particles (in physiological saline) can be colored by adding 150 mg Reactive Blue 4 and Reactive Blue 19, respectively. The first dyeing can be performed at ambient temperature, the latter reaction at 70° C.; after 14 h, the particles can be washed with physiological saline until the solution remains optically colorless.

Example 5 Chemical Incorporation of Dyes to Activated Hydrogels Exhibiting Reactive Groups

A mixture of methyl methacrylate (MMA), diallylurea (DAU) and the crosslinker triethyleneglycol dimethacrylate (TEGDMA) is copolymerized in presence of a radical initiator (lauroyl peroxide, LP) can be performed by suspension polymerization. For example, 100 g freshly distilled MMA, 330 mg LP, 1.43 g TEGDMA, and 1.0 g DAU can be mixed until a clear solution is obtained. The aqueous phase composed of 11.5 g polyvinylalcohol (PVA; 26/88), 2.5 g disodium hydrogen phosphate, and 145 mg sodium dihydrogen phosphate can be dissolved in 500 ml deionized water. Polymerization can be performed by stirring at 130 rpm (initial 250 rpm for 5 to 10 min) at 67° C. for 1 h, than 2 h at 70° C. and finally 80° C. for 2 h. Particle sizes in the range of 50 to 800 μm. Hydrolysis can be performed with 5 g of the particles in 1500 ml ethylene glycol containing 75 g potassium hydroxide under reflux for 2 h. Afterwards, the particles can be washed extensively with deionized water until pH of 7 results. The water can be substituted by physiological saline, and osmolarity measured at 290±50 mOsmol/kg. 20 ml hydrated particles (in physiological saline) can be colored by adding 150 mg Reactive Blue 4 and Reactive Blue 19, respectively. The first dyeing can be performed at ambient temperature, the latter reaction at 70° C.; after 16 h, the particles can be washed with physiological saline until the solution remains optically colorless.

Example 6 Chemical Incorporation of Reactive Dyes to Activated Hydrogels

Reactive Dyes can bind to nucleophilic groups such as amines (primary amines preferred) or hydroxyl groups. To introduce amine groups to an acrylate-based hydrogels, 100 mg dry particles can be hydrated in 5 ml deionized water for 10 to 15 min. Afterwards, 100 mg 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 100 μm ethylene diamine (EDA) can be added and shaken gently for 2 h at ambient temperature. After extensive washing with potable water the beads can be dyed in 5 ml deionized water by adding 200 mg Reactive Blue 4 and Reactive Blue 19, respectively. The first mixture can be kept at room temperature and the latter reaction at 70° C., both over night. The dye solution can be removed and the particles can be washed with potable water and afterwards 3-4 times with 8-9 ml 0.9% NaCl_(aq) until the transport solution (TS) is almost colorless. Different color intensities can be prepared by varying EDA (20 μl to 200 μl), EDC (20 mg to 200 mg), and dye amount (10 mg to 40 0 mg); other colors can be also created by using Reactive Red 11, Reactive Red 180, Reactive Yellow 86, Reactive Yellow 15, Reactive Black 5, and Reactive Blue 21.

Example 7 Chemical Incorporation of Reactive Dyes to Activated Hydrogels

To expand the color palette, a broader range of colors such as green, purple, and orange beads can be prepared as follows. As described above, various mixtures of dyes can be employed together to create the colors of interest, for example: (i) orange can be made by mixing red and yellow (ii) green can be made by mixing blue and yellow, and (iii) purple can be made by mixing blue and red. Dyes can be chosen within the same dye family (Remazol®: Reactive Yellow 15, Reactive Red 180, Reactive Black 5, Reactive Blue 21 and Reactive Blue 19; Procion®: Reactive Red 11, Reactive Yellow 86, Reactive Blue 4). Different color shades can be obtained by using mixtures of different ratios in the range of about 1:100 to about 100:1. Color intensities can be altered by varying EDA (20 μl to 200 μl), EDC (20 mg to 200 mg), and adjusting the total dye amount from about 10 mg to about 400 mg.

Example 8 Chemical Incorporation of Reactive Dyes to Activated Hydrogels

To expand the color palette, a broader range of colors such as green, purple, pink, orange, grey, olive, smurf-blue, brown, ivory, black, burgundy, crimson, turquoise, orange beads can be prepared. Mixtures of at least two dyes can be utilized to create the described colors. Amino activated Reactive Yellow 86, Reactive Yellow 15, Reactive Blue 19, Reactive Red 180, Reactive Orange 78, Reactive Blue 163, Reactive Black 5, Reactive Blue 21, Reactive Blue 4, Reactive Blue 19, and Reactive Red 11 can be used. Different color shades can be obtained by using mixtures of all percentage ratios. Color intensities can be altered by varying EDC (20 mg to 500 mg), and adjusting the total dye amount from about 1 mg to about 400 mg.

Example 9 Chemical Incorporation of Reactive Dyes to Activated Hydrogels

To expand the color palette, a broader range of colors such as green, purple, pink, orange, grey, olive, smurf-blue, brown, ivory, black, burgundy, crimson, turquoise, and orange beads can be prepared. After the first dyeing procedure, additional dyeing procedures can be applied utilizing another dye. Amino activated Reactive Yellow 86, Reactive Yellow 15, Reactive Blue 19, Reactive Red 180, Reactive Orange 78, Reactive Blue 163, Reactive Black 5, Reactive Blue 21, Reactive Blue 4, Reactive Blue 19, and Reactive Red 11 can be utilized, for example. Different color shades can be obtained altering dye amounts (0.1 mg to 20 mg) during the different dyeing procedures. Color intensities can be altered by varying EDC (20 mg to 500 mg), and adjusting the total dye amount from about 1 mg to 100 mg.

Example 10 Physical Incorporation of Iron(III) Chloride as Metal Oxide Precipitate to Hydrogels

Approximately 20 ml particles (900 μm) can be immersed in 80 ml 0.9% aqueous sodium chloride solution (physiological saline). First 2.6 ml aqueous iron(III) chloride (45%) can be added to this suspension, and then followed by 4 ml of 1 molar aqueous iron(II) sulfate. The suspension can be gently shaken for 10 to 15 min to reach diffusion equilibrium. 100 ml of 0.1 molar aqueous sodium hydroxide solution (containing 0.9% sodium chloride) can be added drop wise to allow iron hydroxide precipitation. The particles can be extensively washed with physiological saline. Rusty colored particles can be obtained. Different color intensities can be prepared by varying aqueous iron(III) chloride (45%) from 0.1 ml to 10 ml, 1 molar aqueous iron(II) sulfate from 0.15 ml to 15.5 ml, and aqueous sodium hydroxide from 0.1 molar to 1 molar and 4 ml to 400 ml, respectively.

Example 11 Physical Incorporation of Iron(III) Chloride as Metal Oxide Precipitate to Hydrogels

The particles can be prepared as described above, substituting 0.1 to 1 molar aqueous ammonia (NH_(3aq)) in the place of sodium hydroxide. Different color intensities can be prepared by varying aqueous iron(III) chloride (45%) from 0.1 ml to 10 ml, 1 molar aqueous iron(II) sulfate from 0.15 ml to 15.5 ml, and aqueous ammonia from 0.1 molar to 1 molar and 4 ml to 400 ml, respectively.

Example 12 Physical Incorporation of Iron(III) Chloride as Metal Oxide Precipitate to Hydrogels

The particles can be prepared as described above, as follows. 3 ml hydrated particles (900 μm) can be immersed in 6 ml 0.9% aqueous sodium chloride solution (physiological saline). 2 ml of a saturated aqueous iron(II) sulfate solution (T=20° C.) can be added to the suspension and shaken gently for 10 to 15 min to reach diffusion equilibrium. 2 ml hydrogen peroxide (3%) can be added to the suspension for 5 to 6 min; afterwards the particles can be extensively washed with physiological saline, resulting in brownish colored particles. Different color intensities can be prepared by varying saturated aqueous iron(II) sulfate from 0.1 ml to 10 ml, hydrogen peroxide concentration from 0.1% to 5% utilizing an amount from 0.5 ml to 10 ml.

The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that the specific details are not required in order to practice the invention. The foregoing descriptions of specific embodiments of the present invention are presented for purpose of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Obviously many modifications and variations are possible in view of the above teachings. The embodiments are shown and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the following claims and their equivalent. 

We claim:
 1. Color-coded and size-calibrated polymeric particles, each particle comprising: an acrylate-based hydrogel core incorporating one or more chromophores; and an outer shell comprising a polyphosphazenes having the general formula (I):

in which the n value is an integer from 2 to ∞; R¹ to R⁶ are independently selected from the group consisting of: a substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy, silyl, silyloxy, alkylsulfonyl, alkyl amino, dialkyl amino, ureido, carboxylic acid ester, alkylmonoamidine, alkylbisamidine, alkoxymonoamidine, or alkoxybisamidine, aminoalkyl, haloalkyl, thioalkyl, thioaryl, haloalkoxy, aryloxy, haloaryloxy, alkylthiolate, arylthiolate, alkylsulphonyl, alkylamino, dialkylamino, heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, and combinations thereof, heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, and combinations thereof.
 2. The color-coded and size-calibrated polymeric particles of claim 1, wherein R¹ to R⁶ are selected independently from the group consisting of OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCF₃, OCH₂CF₃, OCH₂CH₂CF₃, OCH₂CF₂CF₃, OCH(CF₃)₂, OCCH₃(CF₃)₂, OCH₂CF₂CF₂CF₃, OCH₂(CF₂)₃CF₃, OCH₂(CF₂)₄CF₃, OCH₂(CF₂)₅CF₃, OCH₂(CF₂)₆CF₃, OCH₂(CF₂)₇CF₃, OCH₂CF₂CHF₂, OCH₂CF₂CF₂CHF₂, OCH₂(CF₂)₃CHF₂, OCH₂(CF₂)₄CHF₂, OCH₂(CF₂)₅CHF₂, OCH₂(CF₂)₆CHF₂, OCH₂(CF₂)₇CHF₂, OCH₂CH═CH₂, OCH₂CH₂CH═CH₂, and any combinations thereof.
 3. The color-coded and size-calibrated polymeric particles of claim 1, wherein the polyphosphazene is poly[bis(2,2,2-trifluoroethoxy)]phosphazene or a derivative of poly[bis(2,2,2-trifluoroethoxy)]phosphazene.
 4. The color-coded and size-calibrated polymeric particles of claim 1, wherein the acrylate-based hydrogel core comprises a polymer selected from the group consisting of poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), copolymers thereof, and combinations thereof.
 5. The color-coded and size-calibrated polymeric particles of claim 1 calibrated to have an average diameter selected from the group consisting of: from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm.
 6. The color-coded and size-calibrated polymeric particles of claim 1, wherein the acrylate-based hydrogel core comprises an agent of interest selected from the group consisting of barium sulfate, an imaging agent, a bioactive agent, a pharmaceutical agent, a contrast agent, a steroid, a hormone, a nucleic acid, an antibiotic, an antiseptic, an analgesic, an anti-neoplastic, an anesthetic, and combinations thereof.
 7. A method of making color-coded and size-calibrated polymeric particles, the method comprising: incorporating one or more chromophores into an acrylate-based hydrogel core; and coating the acrylate-based hydrogel core with a polyphosphazene having the general formula (I):

in which the n value is an integer from 2 to ∞; R¹ to R⁶ are independently selected from the group consisting of: a substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy, silyl, silyloxy, alkylsulfonyl, alkyl amino, dialkyl amino, ureido, carboxylic acid ester, alkylmonoamidine, alkylbisamidine, alkoxymonoamidine, or alkoxybisamidine, aminoalkyl, haloalkyl, thioalkyl, thioaryl, haloalkoxy, aryloxy, haloaryloxy, alkylthiolate, arylthiolate, alkylsulphonyl, alkylamino, dialkylamino, heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, and combinations thereof, heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, and combinations thereof.
 8. The method of claim 7, wherein R¹ to R⁶ are selected independently from the group consisting of OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCF₃, OCH₂CF₃, OCH₂CH₂CF₃, OCH₂CF₂CF₃, OCH(CF₃)₂, OCCH₃(CF₃)₂, OCH₂CF₂CF₂CF₃, OCH₂(CF₂)₃CF₃, OCH₂(CF₂)₄CF₃, OCH₂(CF₂)₅CF₃, OCH₂(CF₂)₆CF₃, OCH₂(CF₂)₇CF₃, OCH₂CF₂CHF₂, OCH₂CF₂CF₂CHF₂, OCH₂(CF₂)₃CHF₂, OCH₂(CF₂)₄CHF₂, OCH₂(CF₂)₅CHF₂, OCH₂(CF₂)₆CHF₂, OCH₂(CF₂)₇CHF₂, OCH₂CH═CH₂, OCH₂CH₂CH═CH₂, and combinations thereof.
 9. The method of claim 7, wherein the acrylate-based hydrogel core comprises a polymer selected from the group consisting of poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), copolymers thereof, and combinations thereof.
 10. The method of claim 7, wherein the color-coded and size-calibrated polymeric particles are calibrated to have an average diameter selected from the group consisting of: from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm.
 11. The color-coded and size-calibrated polymeric particles of claim 1, wherein the acrylate-based hydrogel core comprises an agent of interest selected from the group consisting of barium sulfate, an imaging agent, a bioactive agent, a pharmaceutical agent, a contrast agent, a steroid, a hormone, a nucleic acid, an antibiotic, an antiseptic, an analgesic, an anti-neoplastic, an anesthetic, and combinations thereof.
 12. A method of selective embolization at a site in need of, the method comprising, administering color-coded and size-calibrated particles of claim 1 to a patient in need of. 